Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

Abstract

Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg À1 per day, p.o.) or ARB (olmesartan, 5 mg kg À1 per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-b mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

“…Data from spontaneously hypertensive models suggest that hydralazine was unable to fully inhibit the development of fibrosis, but these findings can be explained by mechanisms independent of RAS activation. 41 In contrast to our findings in the present manuscript, there are examples in the literature of cases in which a reduction in blood pressure to normotensive levels did not abrogate organ damage, suggesting that fibrosis may be blood pressure independent under certain circumstances. 41,42 However, some of these studies had other important differences that should be taken into consideration, such as the presence of metabolic syndrome using genetically mutated mice, in which obesity, dietary supplementation, glucose intolerance and hyperinsulinemia likely contributed to end organ damage.…”

“…41 In contrast to our findings in the present manuscript, there are examples in the literature of cases in which a reduction in blood pressure to normotensive levels did not abrogate organ damage, suggesting that fibrosis may be blood pressure independent under certain circumstances. 41,42 However, some of these studies had other important differences that should be taken into consideration, such as the presence of metabolic syndrome using genetically mutated mice, in which obesity, dietary supplementation, glucose intolerance and hyperinsulinemia likely contributed to end organ damage. 41 The same can be said for a model combining aldosterone administration, uninephrectomy and a high salt diet, in which increased load on the remaining kidney likely contributed to organ damage.…”

“…41,42 However, some of these studies had other important differences that should be taken into consideration, such as the presence of metabolic syndrome using genetically mutated mice, in which obesity, dietary supplementation, glucose intolerance and hyperinsulinemia likely contributed to end organ damage. 41 The same can be said for a model combining aldosterone administration, uninephrectomy and a high salt diet, in which increased load on the remaining kidney likely contributed to organ damage. 42 Furthermore, hydralazine has traditionally been administered in the drinking water, whereas in the current study, we used a more direct administration of hydralazine through an osmotic mini-pump, providing a constant dosage over time.…”

Response to Thornton

“…Moreover, there is no evidence that a large amount of water can cure chronic kidney disease. Indeed, in the article we commented upon previously, Watanabe et al 3 did not provide the drinking and urinary volumes of the animals. However, in our personal experience, the use of ARBs does not increase the urinary volume in OLETF rats (type 2 diabetes model rats with accompanying hypertension).…”

“…Watanabe et al also showed that olmesartan, an ARB, has protective effects on renal function resulting from the suppression of fibrosis in tubulo-interstitial tissue. 3 The increase in the renal plasma flow caused by ARBs is presumably sensitive to renal pathophysiological improvements rather than to excess water from the stimulated drinking behavior. As these rats showed 'hyperfiltration' before the use of ARBs, we concluded that the hemodynamic changes induced by the ARBs influenced renal function in the metabolic syndrome model.…”